Multiple systemic and local factors are required for mammary ductal morphogenesis and some of these factors are under investigation for how they affect breast cancer risk. We have previously demonstrated in the mouse mammary gland that the requirement for estrogens may be mediated by hormone stimulation of an epidermal growth factor receptor ligand. These studies were extended to assess the role of IGF-1 in mammary ductal morphogenesis. Our initial experiments examined the mammary phenotype in mutant mice with various degrees of IGF-1 deficiency. Null mutant (IGF-1-/-) females generally revealed a rudimentary gland with marked inhibition of ductal branching. IGF-1m/m mice, which have a reduced capacity to synthesize IGF-1, formed a mammary gland but exhibited fewer branching structures when compared to age-matched wild- type females of the same genetic background. Treatment of both mutants (ovariectomized) with estradiol failed to correct the deficit of gland extension or branching, which indicates that the phenotype in these mutants is not a consequence of impaired ovarian function. Since growth hormone (GH) decicient (lit/lit) mutant mice also exhibited a greatly reduced rate of mammary development, we speculate that a GH-IGF-1 axis is required for gland morphogenesis. - Breast, epidermal growth factor receptor, estradiol, insulin-like growth factor-1, insulin receptor substrate-1, mammary gland morphogenesis, phosphatidylinositol (PI) 3- kinase